Unravelling The Mechanism Coupling Synaptic Activity With Neurotrophin Signaling In The Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$640,815.00
Summary
Although active brain cells are known to survive for much longer than inactive ones, the mechanism underpinning this essential process has remained elusive. We have uncovered a direct coupling between neuronal activity and survival signals. The purpose of this grant application is to establish the molecular mechanism underpinning this coupling and understand how neuropathic pathogens manage to harness it with devastating effects to the brain.
The Proteins Associated With The Neurotrophin Retrograde Transport Signalling Endosome
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
According to estimates taken from the Australian Bureau of Statistics population projection series, during the next forty years the incidence of Alzheimer's disease or a related dementia in Australia is predicted to increase by 254%. One of the key issues in neurobiology is to understand the mechanisms regulating the survival of nerve cells. Nerve Growth Factor (NGF) acts to cause nerve cell survival by being transported from the target tissue to the cell body in a discrete organelle described a ....According to estimates taken from the Australian Bureau of Statistics population projection series, during the next forty years the incidence of Alzheimer's disease or a related dementia in Australia is predicted to increase by 254%. One of the key issues in neurobiology is to understand the mechanisms regulating the survival of nerve cells. Nerve Growth Factor (NGF) acts to cause nerve cell survival by being transported from the target tissue to the cell body in a discrete organelle described as the Signalling Endosome. This process is termed Retrograde Axonal Transport. The signalling endosome is assembled in the nerve terminal and also contains proteins normally activated by NGF known as Second Messengers. Neurodegenerative diseases, such as Alzheimer's disease, occur due to the death of nerve cells and a disturbance of the retrograde axonal transport of NGF may contribute to this death. NGF has been shown to have clinical potential as it can promote neuronal repair and survival after injury. However clinical trials have demonstrated an unacceptable toxicity for this protein. Therefore, another approach taken to produce the restorative benefits of NGF is to stimulate second messenger pathways downstream from the NGF receptor. This approach could provide important new therapeutic potentials as we can target more selective components of these survival pathways and have a greater chance to find less toxic drugs. This project will identify the second messengers normally accompanying NGF from the nerve terminal which promote nerve cell survival. We will describe the way these proteins are recruited to the signalling endosome. Survival of nerve cells requires the activation of these proteins and we shall determine where this occurs. Understanding the molecular basis for the delivery of the retrograde survival signal in neurons is vital if new therapeutic strategies for the treatment of neurodegenerative disease and traumatic nerve damage are to be developed.Read moreRead less
Vesicular Trafficking Pathways Underpinning Neuronal Secretion And Survival
Funder
National Health and Medical Research Council
Funding Amount
$697,209.00
Summary
Plethora of diseases of the nervous system are caused by defects in vesicular trafficking including neurodegenerative diseases such as Alzheimer’s disease. I will explore the mechanisms underpinning synaptic vesicular trafficking using novel super resolution techniques and reveal the how secretory vesicles traffic to the plasma membrane, undergo exocytosis, and recycle. I will also explain how in the crowded environment of the presynaptic terminals, retrograde cargoes are transported back to the ....Plethora of diseases of the nervous system are caused by defects in vesicular trafficking including neurodegenerative diseases such as Alzheimer’s disease. I will explore the mechanisms underpinning synaptic vesicular trafficking using novel super resolution techniques and reveal the how secretory vesicles traffic to the plasma membrane, undergo exocytosis, and recycle. I will also explain how in the crowded environment of the presynaptic terminals, retrograde cargoes are transported back to the cell body thereby carrying survival signals.Read moreRead less
Glaucoma is a progressive, poorly understood blinding disease with limited treatment options. It is characterised by the death of the nerve cells in the eye whose fibres form the optic nerve. Results obtained in the current proposal will lead to a better understanding of key features of the early stages of the disease and, additionally, will explore the potential of a novel therapeutic approach based on regeneration of damaged nerve fibres within the optic nerve.
Determining Neuronal Connections Involved In Parkinson's Disease And Cocaine Addiction
Funder
National Health and Medical Research Council
Funding Amount
$343,300.00
Summary
Addictive behaviours in response to cocaine use and fine motor coordination that is affected in Parkinson's disease are both controlled by the same type of cells/neurons, i.e., dopamine neurons. However, the circuitry of these neurons varies from where they originate and the type of connections they make. By understanding the neuronal circuitry of these two circuitries in concert we will be able to gain important insight into their roles in adaptive and pathological brain function.
Prevention Of Neuron Death By Targeted Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$195,691.00
Summary
Neurotrophic factors are potent proteins that have the ability to keep nerves alive. They have therefore been used in clinical trials to treat motor neuron disease, but without success. A major reason for this appears to be the way in which the neurotrophic factors are delivered. Direct injections into the blood stream are a convenient way of getting these large proteins into the bloodstream, but this is not their normal mode of action. These proteins are normally provided by cells adjacent to t ....Neurotrophic factors are potent proteins that have the ability to keep nerves alive. They have therefore been used in clinical trials to treat motor neuron disease, but without success. A major reason for this appears to be the way in which the neurotrophic factors are delivered. Direct injections into the blood stream are a convenient way of getting these large proteins into the bloodstream, but this is not their normal mode of action. These proteins are normally provided by cells adjacent to the nerves. We have designed a system that more closely resembles this physiological mode of action which involves the delivery of neurotrophic factor genes, via the bloodstream, to the affected nerves. Once inside the nerves the factors are produced on site and, following their secretion, act locally and directly on the injured nerves.Read moreRead less
Axonal Fusion To Promote Nerve Repair: Molecules And Mechanisms.
Funder
National Health and Medical Research Council
Funding Amount
$456,189.00
Summary
Nerve injuries are in most cases untreatable, leaving patients with high level of disabilities for the rest of their life. Understanding the molecular mechanism regulating nerve regeneration is critical to develop new drugs and design innovative therapies. We discovered molecules that mediates axonal repair by favouring the stitching together of the two separated fragments of an axon. We aim to study how they functions to possibly exploit a similar mechanism of repair for human injuries.
Neurons are highly compartmentalized cell-types. In neurodegenerative diseases such as Alzheimer's disease, the protein Tau that serves a distinct function in one cellular compartment (the axon) accumulates in a massively phosphorylated form elsewhere (somatodendritic compartments and their spines) which is believed to impair neuronal functions. We will investigate how Tau is distributed in health and disease, and determine how this distribution is regulated.
Understanding Changes In Retinal Ganglion Cells Using A Glaucoma Model
Funder
National Health and Medical Research Council
Funding Amount
$88,193.00
Summary
Glaucoma is a pressure related eye disease that is the second leading cause of blindness worldwide. The mechanisms by which glaucoma causes vision loss are poorly understood. At the Centre for Eye Research Australia, we aim to investigate changes within retinal ganglion cells – the neurons which carry light signal from the eye to the brain – using a glaucoma model. We hope to improve understanding of the disease process and highlight new therapeutic options for glaucoma.